rs2229532

chr19-11576317-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001611.5(ACP5):c.661G>A(p.Val221Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00645 in 1,611,542 control chromosomes in the GnomAD database, including 612 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V221V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.035 (313 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (299 hom.)
• Consequence: ACP5 NM_001611.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.26

Genes affected

ACP5 (HGNC:124): (acid phosphatase 5, tartrate resistant) This gene encodes an iron containing glycoprotein which catalyzes the conversion of orthophosphoric monoester to alcohol and orthophosphate. It is the most basic of the acid phosphatases and is the only form not inhibited by L(+)-tartrate. [provided by RefSeq, Aug 2008]

LOC124904638 (HGNC:):

ZNF627 (HGNC:30570): (zinc finger protein 627) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002044946).
• BP6: Variant 19-11576317-C-T is Benign according to our data. Variant chr19-11576317-C-T is described in ClinVar as [Benign]. Clinvar id is 464890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11576317-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACP5	NM_001611.5	c.661G>A	p.Val221Ile	missense_variant	4/5	ENST00000648477.1
LOC124904638	XR_007067140.1	n.105+964C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACP5	ENST00000648477.1	c.661G>A	p.Val221Ile	missense_variant	4/5		NM_001611.5	P3

Frequencies

GnomAD3 genomes AF: 0.0354 AC: 5384 AN: 152100 Hom.: 312 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00976

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.00931 AC: 2313 AN: 248382 Hom.: 132 AF XY: 0.00688 AC XY: 925 AN XY: 134522

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.00484

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.00343 AC: 5012 AN: 1459324 Hom.: 299 Cov.: 33 AF XY: 0.00289 AC XY: 2096 AN XY: 725980

Gnomad4 AFR exome AF: 0.127

Gnomad4 AMR exome AF: 0.00575

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.00691

GnomAD4 genome AF: 0.0354 AC: 5389 AN: 152218 Hom.: 313 Cov.: 32 AF XY: 0.0349 AC XY: 2596 AN XY: 74428

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.00975

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.00642 Hom.: 91

Bravo AF: 0.0407

ESP6500AA AF: 0.128 AC: 566

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0119 AC: 1443

Asia WGS AF: 0.00722 AC: 26 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

Spondyloenchondrodysplasia with immune dysregulation Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	19
Dann	Benign	0.93
DEOGEN2	Benign	0.27	T;T;T;T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.76	D
MetaRNN	Benign	0.0020	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L;L;L;L
MutationTaster	Benign	0.56	D;D;D;D;D
PrimateAI	Benign	0.46	T
Polyphen		0.078	B;B;B;B;B
Vest4		0.095, 0.094
MPC		0.36
ClinPred		0.0037	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2229532; hg19: chr19-11687132; COSMIC: COSV54536780; COSMIC: COSV54536780;